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1.
J Antimicrob Chemother ; 79(7): 1597-1605, 2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38758205

RESUMO

BACKGROUND: Poor adherence to ART and pre-exposure prophylaxis (PrEP) can impact patient and public health. Point-of-care testing (POCT) may aid monitoring and adherence interventions. OBJECTIVES: We report the pharmacokinetics of tenofovir [dosed as tenofovir disoproxil (TDF) and tenofovir alafenamide (TAF)], emtricitabine (FTC), lamivudine (3TC) and dolutegravir (DTG) in plasma and urine following drug cessation to evaluate adherence targets in urine for POCT. METHODS: Subjects were randomized (1:1) to receive DTG/FTC/TAF or DTG/3TC/TDF for 15 days. Plasma and spot urine were collected on Day 15 (0-336 h post final dose). Drug concentrations were quantified using LC-MS, and non-linear mixed-effects models applied to determine drug disposition between matrices and relationship with relevant plasma [dolutegravir protein-adjusted 90% inhibitory concentration (PA-IC90 = 64 ng/mL) and minimum effective concentration (MEC = 324 ng/mL)] and urinary thresholds [tenofovir disoproxil fumarate 1500 ng/mL]. RESULTS: Of 30 individuals enrolled, 29 were included (72% female at birth, 90% Caucasian). Median (range) predicted time to plasma dolutegravir PA-IC90 and MEC were 83.5 (41.0-152) and 49.0 h (23.7-78.9), corresponding to geometric mean (90%) urine concentrations of 5.42 (4.37-6.46) and 27.4 ng/mL (22.1-32.7). Tenofovir in urine reached 1500 ng/mL by 101 h (58.6-205) with an equivalent plasma concentration of 6.20 ng/mL (4.21-8.18). CONCLUSIONS: These data support use of a urinary tenofovir threshold of <1500 ng/mL (tenofovir disoproxil fumarate-based regimens) as a marker of three or more missed doses for a POCT platform. However, due to low dolutegravir concentrations in urine, POCT would be limited to a readout of recent dolutegravir intake (one missed dose).


Assuntos
Fármacos Anti-HIV , Emtricitabina , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Lamivudina , Oxazinas , Piperazinas , Testes Imediatos , Piridonas , Tenofovir , Humanos , Piridonas/urina , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/urina , Compostos Heterocíclicos com 3 Anéis/sangue , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Masculino , Emtricitabina/urina , Emtricitabina/farmacocinética , Emtricitabina/uso terapêutico , Emtricitabina/sangue , Adulto , Piperazinas/urina , Piperazinas/sangue , Lamivudina/urina , Lamivudina/farmacocinética , Lamivudina/sangue , Feminino , Infecções por HIV/tratamento farmacológico , Tenofovir/urina , Tenofovir/farmacocinética , Tenofovir/uso terapêutico , Tenofovir/sangue , Fármacos Anti-HIV/urina , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/uso terapêutico , Pessoa de Meia-Idade , Profilaxia Pré-Exposição/métodos , Adulto Jovem , Plasma/química , Adesão à Medicação
2.
Clin Infect Dis ; 73(9): e3365-e3373, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-32856694

RESUMO

BACKGROUND: Further work is required to understand the intrapulmonary pharmacokinetics of first-line anti-tuberculosis drugs. This study aimed to describe the plasma and intrapulmonary pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol, and explore relationships with clinical treatment outcomes in patients with pulmonary tuberculosis. METHODS: Malawian adults with a first presentation of microbiologically confirmed pulmonary tuberculosis received standard 6-month first-line therapy. Plasma and intrapulmonary samples were collected 8 and 16 weeks into treatment and drug concentrations measured in plasma, lung/airway epithelial lining fluid (ELF), and alveolar cells. Population pharmacokinetic modeling generated estimates of drug exposure (Cmax and AUC) from individual-level post hoc Bayesian estimates of plasma and intrapulmonary pharmacokinetics. RESULTS: One-hundred fifty-seven patients (58% HIV coinfected) participated. Despite standard weight-based dosing, peak plasma concentrations of first-line drugs were below therapeutic drug-monitoring targets. Rifampicin concentrations were low in all 3 compartments. Isoniazid, pyrazinamide, and ethambutol achieved higher concentrations in ELF and alveolar cells than plasma. Isoniazid and pyrazinamide concentrations were 14.6-fold (95% CI, 11.2-18.0-fold) and 49.8-fold (95% CI, 34.2-65.3-fold) higher in ELF than plasma, respectively. Ethambutol concentrations were highest in alveolar cells (alveolar cell-plasma ratio, 15.0; 95% CI, 11.4-18.6). Plasma or intrapulmonary pharmacokinetics did not predict clinical treatment response. CONCLUSIONS: We report differential drug concentrations between plasma and the lung. While plasma concentrations were below therapeutic monitoring targets, accumulation of drugs at the site of disease may explain the success of the first-line regimen. The low rifampicin concentrations observed in all compartments lend strong support for ongoing clinical trials of high-dose rifampicin regimens.


Assuntos
Antituberculosos , Tuberculose , Antituberculosos/uso terapêutico , Teorema de Bayes , Etambutol , Humanos , Isoniazida , Pirazinamida , Tuberculose/tratamento farmacológico
3.
Ther Drug Monit ; 39(6): 654-658, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28953037

RESUMO

BACKGROUND: The aim of this study was to determine the utility of dried blood spots (DBS) compared with conventional plasma collection methods for characterization of efavirenz pharmacokinetics, in the setting of a large-scale, global clinical trial (ENCORE1). METHODS: Six hundred thirty patients were recruited from 38 sites and had single matched whole blood DBS and plasma samples (mid-dose interval) taken at weeks 4 and 12 of treatment. In addition, a subgroup of patients underwent intensive DBS and plasma sampling (0-24 hours) to provide full-profile data for pharmacokinetic parameters. Efavirenz concentrations were determined by validated high-performance liquid chromatography-mass spectrometry methods. A DBS-predicted plasma concentration was derived and linear regression and Bland-Altman plots were used to compare DBS-predicted plasma concentrations with that of measured plasma concentrations. RESULTS: Efavirenz DBS and plasma concentrations were significantly correlated (R = 0.904, P < 0.001; n = 1094), and DBS concentrations were, on average, 53% ± 9.5% lower than plasma. In the main study, the DBS-predicted plasma values significantly underestimated the true measured concentration of efavirenz in plasma; the mean difference (95% confidence interval) between efavirenz DBS-predicted concentrations and measured plasma concentrations was -0.451 mg/L (-0.504 to -0.398) at week 4 (n = 561). However, in the intensive study, the mean difference was only 0.086 mg/L (-0.006 to 0.178) at 12 hours after dose (n = 46) and was not statistically significant. CONCLUSIONS: Our data show a high correlation between measurements of efavirenz concentrations in plasma and in DBS. However, DBS concentrations significantly underestimated the true measured plasma concentrations in the sparse samples taken in this large multinational ENCORE1 trial.


Assuntos
Benzoxazinas/farmacocinética , Teste em Amostras de Sangue Seco/métodos , Monitoramento de Medicamentos/métodos , Inibidores da Transcriptase Reversa/farmacocinética , Alcinos , Cromatografia Líquida de Alta Pressão/métodos , Ciclopropanos , Método Duplo-Cego , Feminino , Humanos , Modelos Lineares , Masculino , Manejo de Espécimes , Espectrometria de Massas em Tandem/métodos , Fatores de Tempo
4.
Clin Infect Dis ; 62(6): 675-682, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26646680

RESUMO

BACKGROUND: Levonorgestrel subdermal implants are preferred contraceptives with an expected failure rate of <1% over 5 years. We assessed the effect of efavirenz- or nevirapine-based antiretroviral therapy (ART) coadministration on levonorgestrel pharmacokinetics. METHODS: This nonrandomized, parallel group, pharmacokinetic evaluation was conducted in three groups of human immunodeficiency virus-infected Ugandan women: ART-naive (n = 17), efavirenz-based ART (n = 20), and nevirapine-based ART (n = 20). Levonorgestrel implants were inserted at baseline in all women. Blood was collected at 1, 4, 12, 24, 36, and 48 weeks. The primary endpoint was week 24 levonorgestrel concentrations, compared between the ART-naive group and each ART group by geometric mean ratio (GMR) with 90% confidence interval (CI). Secondary endpoints included week 48 levonorgestrel concentrations and unintended pregnancies. RESULTS: Week 24 geometric mean levonorgestrel concentrations were 528, 280, and 710 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.53; 90% CI, .50, .55 and nevirapine: ART-naive GMR, 1.35; 90% CI, 1.29, 1.43). Week 48 levonorgestrel concentrations were 580, 247, and 664 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.43; 90% CI, .42, .44 and nevirapine: ART-naive GMR, 1.14; 90% CI, 1.14, 1.16). Three pregnancies (3/20, 15%) occurred in the efavirenz group between weeks 36 and 48. No pregnancies occurred in the ART-naive or nevirapine groups. CONCLUSIONS: Within 1 year of combined use, levonorgestrel exposure was markedly reduced in participants who received efavirenz-based ART, accompanied by contraceptive failures. In contrast, nevirapine-based ART did not adversely affect levonorgestrel exposure or efficacy. CLINICAL TRIALS REGISTRATION: NCT01789879.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Benzoxazinas/uso terapêutico , Anticoncepcionais Femininos/farmacocinética , Infecções por HIV/tratamento farmacológico , Levanogestrel/farmacocinética , Gravidez não Planejada , Adolescente , Adulto , Alcinos , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/efeitos adversos , Anticoncepcionais Femininos/sangue , Ciclopropanos , Interações Medicamentosas , Feminino , Infecções por HIV/etnologia , HIV-1/efeitos dos fármacos , Humanos , Levanogestrel/administração & dosagem , Levanogestrel/efeitos adversos , Levanogestrel/sangue , Nevirapina/uso terapêutico , Gravidez , Inibidores da Transcriptase Reversa/uso terapêutico , Fatores de Tempo , Uganda
5.
Antimicrob Agents Chemother ; 60(5): 2765-70, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26902757

RESUMO

A long-acting injectable form of rilpivirine (RPV) is being evaluated in clinical trials for the prevention of HIV infection. Preclinical testing was undertaken to define RPV pharmacokinetic (PK) and pharmacodynamic (PD) activities in ectocervical and colonic tissue treated in vitro Tenfold dilutions of RPV were added to the basolateral medium of polarized ectocervical and colonic explant tissues. To half the explants, HIV-1BaL was applied to the apical tissue surface. After culture overnight, all the explants were washed and the RPV in the explants not exposed to HIV was quantified using a validated liquid chromatography-mass spectrometry assay. For efficacy, explants exposed to HIV remained in culture, and supernatants were collected to assess viral replication using a p24 enzyme-linked immunosorbent assay. The data were log10 transformed, and PK/PD correlations were determined using GraphPad Prism and SigmaPlot software. The application of RPV to the basolateral medium at 10 µM and 1 µM was effective in protecting ectocervical and colonic tissues, respectively, from HIV infection. When the RPV in paired ectocervical and colonic explant tissues was quantified, significant inverse linear correlations (P < 0.001) between p24 and RPV concentrations were obtained; more viral replication was noted at lower drug levels. Using a maximum effect model, RPV concentrations of 271 nM in ectocervical tissue and 45 nM in colonic tissue were needed to achieve a 90% effective concentration (EC90). These data demonstrate that RPV can suppress HIV infection in mucosal tissue but that higher levels of RPV are needed in female genital tract tissue than in gastrointestinal tract tissue for protection.


Assuntos
Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Rilpivirina/farmacocinética , Rilpivirina/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Humanos , Software
6.
J Antimicrob Chemother ; 71(1): 235-43, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26472771

RESUMO

BACKGROUND: The concentration of antiretrovirals in CSF is often utilized as a surrogate for CNS drug exposure. This measurement does not consider pharmacodynamic or combinative effects of ART. We have developed a novel endpoint measurement to assess antiretroviral activity of CSF from subjects on ART. METHODS: CSF samples were obtained from patients receiving tenofovir/emtricitabine (245/200 mg once daily) with either rilpivirine (25 mg once daily) or lopinavir/ritonavir/maraviroc (400/100/150 mg twice daily) and HIV-uninfected controls. Antiviral activity of ART-containing CSF was assessed in cell cultures using PBMCs and neuro-derived glial (U87) and astrocyte (373) cell lines. Infectivity model half-maximal inhibitory concentration (IMIC50) values were calculated and expressed as -log2IMIC50. Results were correlated with CSF antiretroviral concentrations. RESULTS: Compared with controls, CSF from both ART studies demonstrated in vitro antiretroviral activity in all models. CSF antiretroviral activity of patients on lopinavir/ritonavir/maraviroc was significantly greater than that of patients on rilpivirine [-log2IMIC50 (95% CI) 4.82 (4.74-4.89) versus 3.43 (3.33-3.54) in PBMCs, 3.06 (2.98-3.15) versus 2.56 (2.46-2.65) in U87 cells and 6.00 (6.11-5.88) versus 4.90 (5.09-4.72) in 373 cells, respectively]. Positive correlations were observed for individual CSF antiretroviral activity in different cellular models with CSF concentrations of rilpivirine (P = 0.040 in 373 cells) and lopinavir (P = 0.048 in 373 cells), but not maraviroc. CONCLUSIONS: Antiviral activity of CSF from patients on ART was successfully calculated and was greater with a regimen containing four active drugs compared with three active drugs. The use of neuro-derived cell lines alongside PBMCs to assess the effect of ART on CSF may act as a useful future clinical research tool.


Assuntos
Fármacos Anti-HIV/análise , Líquido Cefalorraquidiano/química , Monitoramento de Medicamentos/métodos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade , Astrócitos/fisiologia , Astrócitos/virologia , Técnicas de Cultura de Células , Células Cultivadas , Feminino , Humanos , Concentração Inibidora 50 , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Neuroglia/fisiologia , Neuroglia/virologia , Cultura de Vírus
7.
Ther Drug Monit ; 37(2): 220-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25162217

RESUMO

BACKGROUND: Efavirenz (EFV) is one of the preferred components of first-line antiretroviral treatment. EFV is characterized by a long plasma half-life (40-55 hours) with large interpatient variability, which raises the potential for individualization of therapy. Analyses of EFV levels in plasma require specialized facilities (cold storage/transport) which, in resource-limited settings, can be problematic; dried blood spots (DBS)-EFV measurements thus provide a cheap easy alternative for therapeutic drug monitoring. Our aim was to develop and validate a liquid chromatography-mass spectrometry method to quantify EFV in DBS collected as part of clinical trials in resource-limited settings. METHODS: DBS for standards, quality control samples, and patient samples were excised and then extracted with ethyl acetate/n-hexane (50/50 vol/vol) after addition of internal standard hexobarbital, and 1 mol/L K2CO3. The extract was evaporated to dryness, the residue reconstituted in mobile phase and analyzed directly by liquid chromatography-mass spectrometry. Gradient elution was on a reverse-phase C18 column using 1 mmol/L ammonium acetate in water and acetonitrile. Quantification was by selected reaction monitoring in negative ionization mode. DBS samples were obtained at several time points over 24 hours from HIV+ patients on either 400 or 600 mg EFV in combination with emtricitabine/tenofovir. RESULTS: The internal standard and EFV eluted at 2.68 and 3.54 minutes, respectively in a 5-minute run time. Matrix effects were minimal (-5.4%). Calibration curves were validated over a concentration range of 25-5000 ng/mL. Intra-assay and interassay variations ranged between 6.7% and 8.7% for imprecision and 100.3% and 104.2% for accuracy. Mean recovery was >64%. The DBS data showed a strong positive correlation with a validated plasma EFV assay (R = 0.9764, P < 0.001). EFV concentrations from DBS were approximately 42% lower than the paired plasma values, and the ratio of blood/plasma did not change over the dosing interval. CONCLUSIONS: The validated assay is now routinely applied to clinical samples measuring DBS EFV for pharmacokinetic analysis. The methodology is robust, accurate, and sensitive.


Assuntos
Fármacos Anti-HIV/sangue , Benzoxazinas/sangue , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas/métodos , Alcinos , Fármacos Anti-HIV/administração & dosagem , Benzoxazinas/administração & dosagem , Calibragem , Ciclopropanos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Infecções por HIV/tratamento farmacológico , Humanos , Reprodutibilidade dos Testes
8.
J Antimicrob Chemother ; 68(6): 1348-53, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23364475

RESUMO

BACKGROUND: Once-daily nucleoside-sparing combination antiretroviral therapy regimens are attractive options for the treatment of HIV infection. However, the pharmacokinetic profiles of such regimens are often not established. METHODS: HIV-infected subjects receiving 245/200 mg of tenofovir/emtricitabine plus 800/100 mg of darunavir/ritonavir once daily with plasma HIV RNA <50 copies/mL were eligible. On day 1 (period 1), 150 mg of maraviroc daily was added and on day 11 (period 2), tenofovir/emtricitabine discontinued. At steady-state (days 10 and 20), intensive pharmacokinetic sampling was undertaken. We assessed (i) the number of subjects with trough (C(trough)) and average (C(avg)) maraviroc concentrations <25 and <75 ng/mL, respectively; (ii) geometric mean (GM) ratios for pharmacokinetic parameters for period 2 versus period 1; and (iii) factors associated with total maraviroc exposure. RESULTS: Eleven subjects completed the study procedures (mean age 49 years; range 35-59 years). In three subjects, maraviroc C(trough) and C(avg) were <25 and <75 ng/mL, respectively (C(avg), 68 ng/mL and C(trough), 14 and 21 ng/mL). Although not statistically significant, a trend was observed towards lower maraviroc, darunavir and ritonavir concentrations in period 2 versus period 1; total maraviroc exposure was 3579 ng·â€Šh/mL (95% CI: 2983-4294) and 2996 ng·â€Šh/mL (95% CI: 2374-3782) in periods 1 and 2, respectively, and the GM ratio was 0.84 (95% CI: 0.67-1.05). Only total ritonavir exposure was significantly associated with total maraviroc exposure (P=0.049; 95% CI: 0.01-0.91). No clinical safety concerns were observed. CONCLUSIONS: Within this novel nucleoside-sparing regimen, maraviroc exposure is dependent on ritonavir exposure, which was slightly reduced in the absence of tenofovir/emtricitabine.


Assuntos
Cicloexanos/efeitos adversos , Cicloexanos/farmacocinética , Inibidores da Fusão de HIV/efeitos adversos , Inibidores da Fusão de HIV/farmacocinética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Inibidores da Protease de HIV/uso terapêutico , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico , Triazóis/efeitos adversos , Triazóis/farmacocinética , Adulto , Terapia Antirretroviral de Alta Atividade , Área Sob a Curva , Contagem de Linfócito CD4 , Cicloexanos/uso terapêutico , Darunavir , Quimioterapia Combinada , Feminino , Inibidores da Fusão de HIV/uso terapêutico , Meia-Vida , Humanos , Masculino , Maraviroc , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral/sangue , Triazóis/uso terapêutico
9.
Antimicrob Agents Chemother ; 56(3): 1427-33, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22183172

RESUMO

There is interest in evaluating the efficacy of lower doses of certain antiretrovirals for clinical care. We determined here the bioequivalence of plasma lamivudine (3TC) and intracellular 3TC-triphosphate (3TC-TP) concentrations after the administration of two different doses. ENCORE 2 was a randomized crossover study. Subjects received 3TC at 300 and 150 mg once daily for 10 days (arm 1; n = 13) or vice versa (arm 2; n = 11), separated by a 10-day washout. Pharmacokinetic (PK) profiles (0 to 24 h) were assessed on days 10 and 30. Plasma 3TC and 3TC-TP levels in peripheral blood mononuclear cells were quantified by high-performance liquid chromatography-tandem mass spectrometry. Within-subject changes in PK parameters (the area under the concentration-time curve from 0 to 24 h [AUC(0-24)], the trough concentration of drug in plasma at 24 h [C(24)], and the maximum concentration of drug in plasma [C(max)]) were evaluated by determining the geometric mean ratios (GMRs) adjusted for study arm, period, and intra-individual variation. Regimens were considered bioequivalent if the 90% confidence interval (90% CI) fell within the range of 0.8 to 1.25. A total of 24 subjects completed the study. The GM (90% CI) 3TC AUC(0-24)), expressed as ng·h/ml, for the 300- and 150-mg doses were 8,354 (7,609 to 9,172) and 4,773 (4,408 to 5,169), respectively. Bioequivalence in 3TC PK following the administration of 300 and 150 mg was not demonstrated: the GMRs for AUC(0-24), C(24), and C(max) were 0.57 (0.55 to 0.60), 0.63 (0.59 to 0.67), and 0.56 (0.53 to 0.60), respectively. The GM (90% CI) 3TC-TP AUC(0-24) values (pmol·h/10(6) cells) for the 300- and 150-mg doses were 59.5 (51.8 to 68.3) and 44.0 (38.0 to 51.0), respectively. Bioequivalence in 3TC-TP PK following the administration of 300 and 150 mg was not demonstrated: the GMRs for AUC(0-24), C(24), and C(max) were 0.73 (0.64 to 0.83), 0.82 (0.68 to 0.99), and 0.70 (0.61 to 0.82), respectively. We found that 3TC at 150 mg is not bioequivalent to the standard regimen of 300 mg, indicating that saturation of cytosine phosphorylation pathways is not achieved at a dose of 150 mg.


Assuntos
Citidina Trifosfato/análogos & derivados , Didesoxinucleotídeos/farmacocinética , Lamivudina/análogos & derivados , Inibidores da Transcriptase Reversa/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Área Sob a Curva , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Citidina Trifosfato/sangue , Citidina Trifosfato/farmacocinética , Didesoxinucleotídeos/sangue , Esquema de Medicação , Feminino , Humanos , Lamivudina/sangue , Lamivudina/farmacocinética , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/sangue , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Reino Unido , Adulto Jovem
10.
Pharmacogenomics ; 20(4): 217-223, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30767719

RESUMO

AIM: Treatment and prevention of mother-to-child transmission of HIV in pregnancy utilizes tenofovir (TFV) and emtricitabine (FTC) as NRTI backbone in combination with a third agent from a different class. We hypothesized that combined effect of pregnancy and pharmacogenetics significantly changes TFV and FTC pharmacokinetics (PK). Therefore, this study aims to evaluate the role of SNPs of transporters (ABCC2 and ABCC4) on TFV and FTC PK during pregnancy. METHOD: 61 pregnant or postpartum women on TFV and FTC were selected from a group of pregnant and postpartum Nigerian women and both SNPs and drug levels were evaluated. RESULTS: Pregnancy decreases TFV plasma concentration by 26% (log10 ß = -0.131 [-0.228, -0.034; p = 0.009] at median [range] time-point postdose 14 [7-18.5h]). FTC concentration in individuals with ABCC2 12:g.154962860T>C TT genotype were one- to twofold higher than heterozygous (CT) and homozygous (CC) women. All other evaluated SNPs were not significant. CONCLUSION: Pregnancy decreased TFV concentration and significant relationship was found between FTC and ABCC2 12:g.154962860T>C wild-type allele. However, the interplay between pregnancy and pharmacogenetics on TFV and FTC PK is unclear but require further evaluation.


Assuntos
Emtricitabina/administração & dosagem , Infecções por HIV/tratamento farmacológico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Tenofovir/administração & dosagem , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Emtricitabina/efeitos adversos , Emtricitabina/farmacocinética , Feminino , Genótipo , Infecções por HIV/genética , Infecções por HIV/transmissão , Infecções por HIV/virologia , Humanos , Transmissão Vertical de Doenças Infecciosas , Leucócitos Mononucleares/efeitos dos fármacos , Proteína 2 Associada à Farmacorresistência Múltipla , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Tenofovir/efeitos adversos , Tenofovir/farmacocinética , Adulto Jovem
11.
Antivir Ther ; 24(3): 229-233, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30728322

RESUMO

BACKGROUND: Physiological changes during pregnancy can have a significant impact on antiretroviral pharmacokinetics (PK), which may result in reduced drug efficacy. Here we describe the PK of darunavir/ritonavir (DRV/r) 800/100 once daily in a cohort of pregnant women undergoing routine therapeutic drug monitoring (TDM) as well as transplacental passage of DRV by measuring and comparing cord blood and maternal blood samples at delivery. METHODS: Pregnant HIV-positive women received DRV/r as part of routine pre-natal care. Demographic and clinical data were collected. DRV plasma concentrations [DRV] were determined in the first (T1), second (T2) and third (T3) trimester and at postpartum (PP). The target concentration was 550 ng/ml. Where possible, paired maternal and cord blood samples were taken at delivery. RESULTS: A total of 33 women were enrolled. Samples were taken 14-20 h post-dose and measured concentrations were extrapolated to 24 h post-dose. At the time nearest to delivery, all but four had undetectable plasma viral loads (pVL). [DRV] were determined in 1 (T1); 14 (T2); 32 (T3) and 29 (PP). 1 sample was <550 ng/ml at T2, 6 at T3 and 3 at PP. [DRV] were significantly lower at T2/T3 relative to PP. CONCLUSIONS: [DRV] in T2 and T3 were 36-55% when compared with PP. However, DRV PK in pregnancy were not associated with a lack of virological suppression at delivery as of the 33 patients enrolled in this study, 31 had no HIV transmission from mother to child. Data regarding two candidates were not available as they delivered in a separate health-care facility.


Assuntos
Antirretrovirais/farmacocinética , Darunavir/farmacocinética , Infecções por HIV/tratamento farmacológico , HIV-1 , Complicações Infecciosas na Gravidez/tratamento farmacológico , Ritonavir/farmacocinética , Adulto , Antirretrovirais/administração & dosagem , Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Darunavir/administração & dosagem , Darunavir/uso terapêutico , Monitoramento de Medicamentos , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Gravidez , Complicações Infecciosas na Gravidez/virologia , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , Resultado do Tratamento , Carga Viral , Adulto Jovem
13.
Artigo em Inglês | MEDLINE | ID: mdl-29579732

RESUMO

Levonorgestrel (LNG) is a synthetic progestin that is available in oral contraceptive tablets, a subdermal implant, and an intrauterine system for contraception. LNG pharmacokinetics are a pivotal determinant of contraceptive efficacy and essential in assessing drug-drug interactions influencing LNG exposure following different routes of LNG administration. A highly sensitive LC-MS/MS method was developed and validated to quantify levonorgestrel in human plasma. Liquid-liquid extraction was utilized with a sample volume of 500 µL to extract levonorgestrel from plasma. Chromatographic separation of LNG was achieved with a Fortis™ C18 (3 µm: 100 mm × 2.1 mm) reverse phase analytical column. The mobile phases consisted of de-ionized water plus 0.1% NH4OH (100:0.1%, v/v) (A), and methanol plus 0.1% NH4OH (100:0.1%, v/v) (B) delivered as a gradient at a flow rate of 400 µL/min. Detection of LNG and internal standard (D-(-)-norgestrel-d7) was achieved using positive polarity mode monitoring at 313.2-245.2 amu and 320.1-251.2 amu, respectively. The assay was linear over the calibration range of 49.6 to 1500 pg/mL. This method was used to quantify plasma LNG released by subdermal implant in support of a drug interaction study among women with HIV receiving efavirenz- or nevirapine-based antiretroviral therapy.


Assuntos
Cromatografia Líquida/métodos , Anticoncepcionais Femininos/sangue , Levanogestrel/sangue , Espectrometria de Massas em Tandem/métodos , Anticoncepcionais Femininos/química , Anticoncepcionais Femininos/farmacocinética , Implantes de Medicamento , Feminino , Infecções por HIV , Humanos , Levanogestrel/química , Levanogestrel/farmacocinética , Modelos Lineares , Extração Líquido-Líquido , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
14.
Bioanalysis ; 10(23): 1933-1945, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30450920

RESUMO

Aim: A novel, sensitive and reproducible method for quantification of dolutegravir (DTG) in dried breast milk spots (DBMS) was developed and validated for use in clinical studies. Its application enabled measurement of DTG pharmacokinetics in breastfeeding mothers and their infants. Results/methodology: Sample extraction was by liquid-liquid extraction using tert-butyl methy-ether, with DTG-d5 as an internal standard. DTG was eluted on a reverse phase C18 Waters XBridge (3.5 µm: 2.1 × 50 mm) column using a gradient mobile phase consisting of 0.1% formic acid in deionised water or methanol. The assay was validated over a calibration range of 10-4000 ng/ml. Conclusion: Stability, inter and intra-assay variability were acceptable according to FDA and EMA bioanalytical method guidelines. The assay is robust, accurate, precise and can be reliably applied for analysis of clinical samples in trials from low resource settings.

15.
AIDS ; 30(1): 145-9, 2016 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-26372479

RESUMO

OBJECTIVES: To assess the extent of nondisclosure of known HIV status among sexual health clinic attendees and to quantify the impact of nondisclosure on estimates of undiagnosed HIV prevalence and of the proportion of patients remaining undiagnosed on leaving the clinic. METHODS: Serum samples from the unlinked anonymous survey of clinic attendees' archive were tested for antiretrovirals. Estimates of undiagnosed HIV were adjusted using the findings. RESULTS: Antiretrovirals were detected in 27% of samples taken from 'previously undiagnosed' attendees, who did not have an HIV test but were HIV positive as detected by unlinked anonymous testing, indicating nondisclosure; 24% of such samples from MSM had antiretrovirals present compared with 32% of heterosexual men and women. Antiretrovirals were detected in 33% of samples from London clinics and in 21% from non-London clinics. Following adjustment, the estimated prevalence of undiagnosed HIV decreased nonsignificantly from 3.04% (95% confidence interval 2.71-3.41) to 2.66% (2.35-3.01) among men who have sex with men (MSM), 0.31% (0.26-0.37) to 0.30% (0.25-0.36) in heterosexual men and 0.40% (0.35-0.46) to 0.37% (0.32-0.43) in women; 7% of MSM who do not have an HIV test at a clinic visit will be infected with HIV and remain unaware of their infection. CONCLUSION: Nondisclosure of HIV status to healthcare professionals occurs among clinic attendees. Adjustment for nondisclosure results in a small, nonsignificant decrease in the prevalence of undiagnosed HIV estimated from the unlinked anonymous survey in sexual health clinics. Testing the population of MSM not having an HIV test remains a priority as levels of undiagnosed HIV are high.


Assuntos
Assistência Ambulatorial , Antirretrovirais/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Adulto , Inglaterra/epidemiologia , Feminino , Infecções por HIV/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Inquéritos e Questionários , Adulto Jovem
16.
Bioanalysis ; 6(14): 1907-21, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25158963

RESUMO

BACKGROUND: A sensitive, specific and robust liquid chromatography-tandem mass spectrometry method has been developed and validated for the quantification of rilpivirine in human plasma, genital/rectal biofluids and mucosal tissues. METHODS: Plasma and tissue samples were extracted using protein precipitation (acetonitrile/water; 5:1 v/v), and genital/rectal biofluids absorbed onto ophthalmic swabs were extracted using liquid-liquid extraction (hexane/ethyl acetate; 80:20 v/v). A stable isotope-labeled internal standard ((13)C-d4-RPV) was used, and the assay was validated over a concentration range of 0.5-400 ng/ml. CONCLUSION: Inter- and intra-assay precision and accuracy met the acceptance as per US FDA bioanalytical guidelines. The validated assay has been used for the determination of rilpivirine concentrations in these matrices as part of an exploratory pharmacokinetic study investigating the suitability of a long-acting formulation of rilpivirine for pre-exposure prophylaxis.


Assuntos
Fármacos Anti-HIV/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Nitrilas/farmacocinética , Pirimidinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Fármacos Anti-HIV/análise , Fármacos Anti-HIV/sangue , Líquidos Corporais/metabolismo , Feminino , Humanos , Masculino , Mucosa/metabolismo , Nitrilas/análise , Nitrilas/sangue , Pirimidinas/análise , Pirimidinas/sangue , Reprodutibilidade dos Testes , Rilpivirina
17.
Artigo em Inglês | MEDLINE | ID: mdl-23831525

RESUMO

A sensitive high-performance reverse phase liquid chromatography-positive ion electrospray tandem mass spectrometry method was developed and validated for the quantification of telaprevir and its inactive R-diastereomer (VRT-127394) in human plasma. The analytes and the internal standard (telaprevir-d11) were extracted from plasma by liquid-liquid extraction using tert-Butyl methyl ether (TBME). Chromatographic separation was achieved on a reversed-phase Accucore C18 column with a gradient programme consisting of water:ammonia (25%), 100:0.01 (v/v) (mobile phase A) and ACN:MeOH:ammonia (25%), 15:85:0.01 (v/v/v) (mobile phase B). The MS acquisition was performed with selective reaction monitoring mode using the respective [M+H](+) ions, m/z 680.59→322.42 for telaprevir and VRT-127394, and 691.15→110.13 for telaprevir-d11. The assay exhibited a linear dynamic range of 5-5000ng/mL for telaprevir and VRT-127394. Acceptable precision (%RSD<6.5%) and accuracy (94-108%) were obtained for concentrations over the range of the standard curve. A procedure was established to stabilise the plasma to prevent ex vivo interconversion of the isomers.


Assuntos
Antivirais/sangue , Hepacivirus/enzimologia , Oligopeptídeos/sangue , Inibidores de Proteases/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Antivirais/química , Cromatografia Líquida/métodos , Hepatite C/tratamento farmacológico , Humanos , Limite de Detecção , Oligopeptídeos/química , Inibidores de Proteases/química , Estereoisomerismo , Espectrometria de Massas em Tandem/métodos
18.
Antivir Ther ; 16(8): 1139-47, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22155898

RESUMO

HIV resides within anatomical 'sanctuary sites' where local drug exposure and viral dynamics may differ significantly from the systemic compartment. Widespread implementation of antiretroviral therapy has seen a significant decline in the incidence of mother-to-child transmission (MTCT) of HIV. In addition to suppression of maternal plasma/genital viral loads, antiretroviral agents that cross the placenta and achieve adequate concentrations in the fetal compartment may exert a greater prophylactic effect. Penetration of antiretrovirals in the fetal compartment is expressed by accumulation ratios derived from the measurement of drug concentrations in paired maternal plasma and umbilical cord samples. The nucleoside analogues and nevirapine accumulate extensively in cord blood and in the surrounding amniotic fluid, whereas the protease inhibitors (PIs) exhibit low-to-moderate placental accumulation. Early data suggest that high placental/neonatal concentrations are achieved with raltegravir, but to a lesser extent with etravirine and maraviroc (rank order of accumulation: raltegravir/nucleoside reverse transcriptase inhibitor [tenofovir > zidovudine/lamivudine/emtricitabine/stavudine/abacavir] > non-nucleoside reverse transcriptase inhibitor [nevirapine > etravirine] > PI > maraviroc/enfuvirtide). More comprehensive in vivo pharmacokinetic data are required to justify the potential use of these agents as safe and effective options during pregnancy.


Assuntos
Líquido Amniótico/efeitos dos fármacos , Fármacos Anti-HIV/farmacocinética , Sangue Fetal/efeitos dos fármacos , Feto/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Placenta/efeitos dos fármacos , Complicações Infecciosas na Gravidez/prevenção & controle , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/uso terapêutico , Adulto , Líquido Amniótico/virologia , Fármacos Anti-HIV/uso terapêutico , Cicloexanos/farmacocinética , Cicloexanos/uso terapêutico , Enfuvirtida , Feminino , Sangue Fetal/virologia , Feto/virologia , Proteína gp41 do Envelope de HIV/farmacocinética , Proteína gp41 do Envelope de HIV/uso terapêutico , Inibidores da Fusão de HIV/farmacocinética , Inibidores da Fusão de HIV/uso terapêutico , Infecções por HIV/sangue , Infecções por HIV/virologia , Inibidores de Integrase de HIV/farmacocinética , Inibidores de Integrase de HIV/uso terapêutico , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/uso terapêutico , HIV-1/fisiologia , Humanos , Lamivudina/farmacocinética , Lamivudina/uso terapêutico , Maraviroc , Nevirapina/farmacocinética , Nevirapina/uso terapêutico , Organofosfonatos/farmacocinética , Organofosfonatos/uso terapêutico , Fragmentos de Peptídeos/farmacocinética , Fragmentos de Peptídeos/uso terapêutico , Placenta/virologia , Gravidez , Pirrolidinonas/farmacocinética , Pirrolidinonas/uso terapêutico , Raltegravir Potássico , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/uso terapêutico , Tenofovir , Triazóis/farmacocinética , Triazóis/uso terapêutico , Carga Viral/efeitos dos fármacos , Zidovudina/farmacocinética , Zidovudina/uso terapêutico
19.
Antivir Ther ; 16(8): 1149-67, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22155899

RESUMO

HIV resides within anatomical 'sanctuary sites', where local drug exposure and viral dynamics may differ significantly from the systemic compartment. Suboptimal antiretroviral concentrations in the genital tract may result in compartmentalized viral replication, selection of resistant mutations and possible re-entry of wild-type/resistant virus into the systemic circulation. Therefore, achieving adequate antiretroviral exposure in the genital tract has implications for the prevention of sexual and vertical transmission of HIV. Penetration of antiretrovirals in the genital tract is expressed by accumulation ratios derived from the measurement of drug concentrations in time-matched seminal plasma/cervicovaginal fluid and plasma samples. Penetration varies by gender and may be drug (as opposed to class) specific with high interindividual variability. Concentrations in seminal plasma are highest for nucleoside analogues and lowest for protease inhibitors and efavirenz. Seminal accumulation of newer agents, raltegravir and maraviroc, is moderate (rank order of accumulation is nucleoside/nucleotide reverse transcriptase inhibitors [lamivudine/zidovudine/tenofovir/didanosine > stavudine/abacavir] > raltegravir > indinavir/maraviroc/nevirapine >> efavirenz/protease inhibitors [amprenavir/atazanavir/darunavir > lopinavir/ritonavir > saquinavir] > enfuvirtide). In the female genital tract, the nucleoside analogues exhibit high accumulation ratios, whereas protease inhibitors have limited penetration; however, substantial variability exists between individuals and study centres. Second generation non-nucleoside reverse transcriptase inhibitor etravirine, and maraviroc and raltegravir, demonstrate effective accumulation in cervicovaginal secretions (rank order of accumulation is nucleoside/nucleotide reverse transcriptase inhibitor [zidovudine/lamivudine/didanosine > emtricitabine/tenofovir] > indinavir > maraviroc/raltegravir/darunavir/etravirine > nevirapine/abacavir > protease inhibitors [amprenavir/atazanavir/ritonavir] > lopinavir/stavudine/efavirenz > saquinavir).


Assuntos
Fármacos Anti-HIV/farmacocinética , Permeabilidade Capilar/fisiologia , Genitália Feminina/efeitos dos fármacos , Genitália Masculina/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Adulto , Fármacos Anti-HIV/uso terapêutico , Líquidos Corporais/efeitos dos fármacos , Líquidos Corporais/virologia , Feminino , Genitália Feminina/anatomia & histologia , Genitália Feminina/fisiologia , Genitália Masculina/anatomia & histologia , Genitália Masculina/fisiologia , Inibidores da Fusão de HIV/farmacocinética , Inibidores da Fusão de HIV/uso terapêutico , Infecções por HIV/sangue , Infecções por HIV/transmissão , Infecções por HIV/virologia , Inibidores de Integrase de HIV/farmacocinética , Inibidores de Integrase de HIV/uso terapêutico , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/uso terapêutico , HIV-1/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/uso terapêutico , Sêmen/efeitos dos fármacos , Sêmen/virologia , Fatores Sexuais , Carga Viral/efeitos dos fármacos
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